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The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock

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Abstract

Objective

To investigate the role of the inducible nitric oxide synthase activation-induced excess nitric oxide formation on the rate of hepatic glucose production during fully resuscitated murine septic shock.

Design

Prospective, controlled, randomized animal study.

Setting

University animal research laboratory.

Subjects

Male C57Bl/6 and B6.129P2-Nos2tm1Lau/J (iNOS−/−) mice.

Interventions

Fifteen hours after cecal ligation and puncture, anesthetized, mechanically ventilated and instrumented mice (wild-type controls, n = 13; iNOS−/−, n = 12; wild-type mice receiving 5 mg·kg−1 i.p. of the selective iNOS inhibitor GW274150 immediately after cecal ligation and puncture, n = 8) received continuous i.v. hydroxyethylstarch and norepinephrine to achieve normotensive and hyperdynamic hemodynamics.

Measurements and results

Measurements were recorded 18, 21 and 24 h after cecal ligation and puncture. Liver microcirculatory perfusion and capillary hemoglobin O2 saturation (laser Doppler flowmetry and remission spectrophotometry) were well maintained in all groups. Despite significantly lower norepinephrine doses required to achieve the hemodynamic targets, the rate of hepatic glucose production (gas chromatography–mass spectrometry measurements of tissue isotope enrichment during continuous i.v. 1,2,3,4,5,6-13C6-glucose infusion) at 24 h after cecal ligation and puncture was significantly higher in both iNOS−/− and GW274150-treated mice, which was concomitant with a significantly higher hepatic phosphoenolpyruvate carboxykinase activity (spectrophotometry) in these animals.

Conclusions

In normotensive, hyperdynamic septic shock, both pharmacologic and genetic deletion of the inducible nitric oxide synthase allowed maintenance of hepatic glucose production, most likely due to maintained activity of the key regulatory enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase.

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Authors and Affiliations

  1. Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum, Parkstrasse 11, 89073, Ulm, Germany

    Gerd Albuszies, Josef Vogt, Ulrich Wachter, Sandra Weber, Michael Georgieff, Peter Radermacher & Eberhard Barth

  2. Department of Experimental Medicine and Nephrology, The William Harvey Research Institute, London, UK

    Christoph Thiemermann

  3. Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble, France

    Xavier M. Leverve

Authors
  1. Gerd Albuszies
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  2. Josef Vogt
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  3. Ulrich Wachter
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  4. Christoph Thiemermann
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  5. Xavier M. Leverve
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  6. Sandra Weber
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  7. Michael Georgieff
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  8. Peter Radermacher
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  9. Eberhard Barth
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Corresponding author

Correspondence to Peter Radermacher.

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G. Albuszies and J. Vogt contributed equally to this article.

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Albuszies, G., Vogt, J., Wachter, U. et al. The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock. Intensive Care Med 33, 1094–1101 (2007). https://doi.org/10.1007/s00134-007-0638-7

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  • DOI: https://doi.org/10.1007/s00134-007-0638-7

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